Pharmaceutical suspensions are uniform dispersions of solid drug particles in a vehicle in which the drug has minimum solubility. These are usually formulated to improve chemical stability of drug, mask the unpleasant taste and in instances where a liquid dosage form is preferred (easier to swallow, flexibility of administration in a range of doses) over a solid dosage form. Suspension as a dosage form however is associated with issues such as microbial growth, sedimentation and non-uniformity of dose, high cost of manufacturing, difficult to carry etc. For administration of suspensions to children a special oral syringe or dossator needs to be provided which requires care during administration such as proper measurement of the dose, cleaning of the syringe after use, etc. Therefore an alternative dosage form is desired.
Solid oral dosage forms are most convenient from patient as well as from manufacturing chemist's perspective. They ensure uniformity of dosage, are more robust, have less microbiological issues compared to liquid dosage forms. However immediate release tablets cannot act as a substitute for suspension. Thus, there is a need for a formulation, which overcomes the problems associated with the swallowing of solid dosage forms and act as a viable substitute for suspensions. One such dosage form is dispersible tablet. Dispersible tablets as defined in Ph. Eur. are uncoated or film coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. Typically a dispersible tablet is dispersed in about 5-15 ml of water and the resulting dispersion is administered to the patient. Dispersible tablets are required to disintegrate within 3 minutes in water at 15-25° C. Also the dispersion produced from a dispersible tablet should pass through a sieve screen with a nominal mesh aperture of 710 microns. The dosage form provides advantages of both tablets and liquid formulations. These are convenient to carry, easy to manufacture and more stable.
U.S. Pat. No. 5,256,699 describes a dispersible solid drug formulation of finely divided diclofenac free acid along with a disintegrant and diluent. Dispersible tablets of macrolide antibiotics are described in US patent application 20020061333. U.S. Pat. No. 5,698,226 describes a dispersible tablet of acyclovir or lamotrigine comprising a dispersing agent such as smectite. A dispersible tablet formulation of lamotrigine without use of swellable clay is claimed in PCT application WO 05051350. A roller compression process for production of dispersible tablets of beta lactam antibiotics is discussed in PCT application WO 05115347 whereas direct compression process is elaborated in EP 1086689.
All above-mentioned patents describe dispersible tablets made using varied compositions and processes. However one common limitation of these formulations is settling of the insoluble solids at the bottom or sides of container of the prepared dispersion, which may lead to a loss of part of the drug during administration, resulting in suboptimal dosing.
Sedimentation of particles in a suspension is governed by several factors: particle size, density of the particles and density and viscosity of the vehicle. The velocity of sedimentation of particles in a suspension can be determined by using Stoke's equation:v=[2r2(D−d)g]/9ηWhere:v=velocity of sedimentationr=radius of the particleg=acceleration of gravityD=density of the particled=density of the vehicleη=viscosity of the vehicle
According to the Stoke's equation, the velocity of sedimentation of particles in a suspension can be reduced by increasing the viscosity of the vehicle.
PCT application WO0145671 discloses an oral suspension formulation of oxcarbazepine, which attains a viscosity of 5-52 mPas upon shaking. The formulation, however being a suspension, has all the above mentioned limitations. Moreover due to instability of oxcarbazepine, special precautions are required at the manufacturing stage which include purging with nitrogen, inert atmosphere etc. These steps not only complicate the process but also make it time-consuming and expensive.
U.S. Pat. No. 4,886,669 discloses composition of one or more pharmacologically pharmacologically active ingredients in the form of water-dispersible tablet comprising of active ingredient in the form of microparticles. The formulation also contains at least one disintegrant and a swellable material, which generates high viscosity when it comes in contact with water. The microparticles are coated and have a specific size range. Microparticles are prepared for controlled release or taste masking purposes. A special process is employed for manufacturing of the microparticles that is tedious, complicated, and time consuming. To ensure reduced sedimentation, use of high concentrations of polymers is necessary. This may affect the dispersibility. Moreover increase in viscosity alone cannot be regarded as a parameter for dosage form uniformity as there still remains a possibility of sedimentation of high density microparticles. Therefore, the important parameter for uniformity of dosage is the sedimentation rate.
None of the prior art addresses the issue of sedimentation of the active ingredient after formation of a suspension from the dispersible tablet, leading to non-uniformity of dosage. The present inventors have developed a composition of a pharmacologically active ingredient in the form of a dispersible tablet, which, when dispersed in water, gives a homogeneous dispersion with a low sedimentation rate. It is known in the prior art that increasing the viscosity of the vehicle decreases the sedimentation rate. It is also known in the art that use of high viscosity excipients tend to retard the disintegration time of a tablet. It was surprisingly found that selective use excipients in the present invention reduces the sedimentation rate of solids in the dispersion without altering the dispersibility of the composition and ensures uniformity of the dose and thus improves patient compliance.